Wilms tumor gene (WT1 gene) is a zinc-finger transcription factor-encoding gene. WT1 gene is known to have four isoforms distinguished by the presence or absence of 17 amino acids (17AA) inserted at the 5′-side site of the two alternative splicing sites of the gene, as well as by the presence or absence of three amino acid residues between zinc fingers 3 and 4.
Wilms tumor gene (WT1 gene) was isolated as a causative gene of pediatric kidney tumor (Non-patent Documents 1 and 2). Since some deletions and mutations in this gene have been found in Wilms tumor, it has been believed that this gene is a tumor suppressor gene.
However, a number of reports by the present inventors suggest that WT1 gene exerts an oncogene-like function rather than functions as a tumor suppressor gene. It has been revealed that almost all leukemia cells express high levels of the nonmutated wild type WT1 gene, and the expression level in leukemia is reciprocally correlated with the prognosis of patients (Non-patent Documents 3 and 4); antisense WT1 DNA specifically suppresses the growth of leukemia cells (Non-patent Document 5); forced expression of the WT1 gene results in suppression of the differentiation of mouse normal bone marrow precursor cells and bone marrow precursor cell line 32D C13 into neutrophils, and the cells began proliferating as a result (Non-patent Document 6); etc. These findings suggest that the WT1 gene is involved in the leukemogenic conversion of hematopoietic cells. The present inventors have also reported that the wild type WT1 gene is expressed at high levels in various types of solid cancers (Non-patent Documents 7 to 14).
The present inventors believe that the WT1 gene would be useful for the development of tumor-specific molecular target therapy if expression of the gene can be efficiently suppressed. To date, no tumor-specific molecular target therapy that targets WT1 has been known.
[Non-patent Document 1] Call K M, et al.: Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 60: 509, 1990
[Non-patent Document 2] Gessler M, et al.: Homozygous deletion in Wilms tumours of a zinc-finger gene identified by chromosome jumping. Nature 343′. 774, 1990
[Non-patent Document 3] Inoue K, et al.: WT1 as a new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood 84: 3071, 1994
[Non-patent Document 4] Inoue K, et al.: Aberrant overexpression of the Wilms tumor gene (WT1) in human leukemia. Blood 89: 1405, 1997
[Non-patent Document 5] Yamagami T, Sugiyama H, Inoue K, Ogawa H, Tatekawa T, Hirata M, Kudoh T, Akiyama T, Murakami A, Maekawa T. Growth inhibition of human leukemic cells by WT1 (Wilms tumor gene) antisense oligodeoxynucleotides: implications for the involvement of WT1 in leukemogenesis. Blood. 1996 Apr. 1; 87(7):2878-84.[Non-patent Document 6] Inoue K, et al.: Wilms' tumor gene (WT1) competes with differentiation-inducing signal in hematopoietic progenitor cells. Blood 91:2969, 1998[Non-patent Document 7] Oji, Y., Ogawa, H., Tamaki, H., Oka, Y., Tsuboi, A., Kim, E. H., Soma, T., Tatekawa, T., Kawakami, M., Asada, M., Kishimoto, T., and Sugiyama, H. Expression of the Wilms' tumor gene WT1 in solid tumors and its involvement in tumor cell growth. Japanese Journal of Cancer Research, 90: 194-204, 1999.[Non-patent Document 8] Oji, Y, Miyoshi, S., Maeda, H., Hayashi, S., Tamaki, H., Nakatsuka, S., Yao, M., Takahashi, E., Nakano, Y, Hirabayashi, H., Shintani, Y., Oka, Y, Tsuboi, A., Hosen, N., Asada, M., Fujioka, T., Murakami, M., Kanato, K., Motomura, M., Kim, E. H., Kawakami, M., Ikegame, K., Ogawa, H., Aozasa, K., Kawase, I., and Sugiyama, H. Overexpression of the Wilms' tumor gene WT1 in de novo lung cancers. International Journal of Cancer, 100: 304-308, 2002.[Non-patent Document 9] Ueda, T., Oji, Y., Naka, N., Nakano, Y, Takahashi, E., Koga, S., Asada, M., Ikeba, A., Nakatsuka, S., Abeno, S., Hosen, N., Tomita, Y, Aozasa, K., Tamai, N., Myoui, A., Yoshikawa, H., and Sugiyama, H. Overexpression of the Wilms' tumor gene WT1 in human bone and soft-tissue sarcomas. Cancer Science, 94: 271-276, 2003.[Non-patent Document 10] Oji, Y., Inohara, H., Nakazawa, M., Nakano, Y., Akahani, S., Nakatusuka, S., Koga, S., Abeno, S., Honjo, Y., Yamamoto, Y., Iwai, S., Yoshida, K., Oka, Y., Ogawa, H., Yoshida, J., Aozasa, K., Kubo, T., and Sugiyama, H. Overexpression of the Wilms' tumor gene WT1 in head and neck squamous cell carcinoma. Cancer Science, 94: 523-529, 2003.[Non-patent Document 11] Oji, Y, Miyoshi, Y, Koga, S., Nakano, Y, Ando, A., Nakatuska, S., Ikeba, A., Takahashi, E., Sakaguchi, N., Yokota, A., Hosen, N., Ikegame, K., Kawakami, M., Tsuboi, A., Oka, Y., Ogawa, H., Aozasa, K., Noguchi, S., and Sugiyama, H. Overexpression of the Wilms' tumor gene WT1 in primary thyroid cancer. Cancer Science, 94: 606-611, 2003.[Non-patent Document 12] Oji, Y., Yamamoto, H., Nomura, M., Nakano, Y., Ikeba, A., Nakatsuka, S., Abeno, S., Kiyotoh, E., Jomgeow, T., Sekimoto, M., Nezu, R., Yoshikawa, Y., Inoue, Y., Hosen, N., Kawakami, M., Tsuboi, A., Oka, Y, Ogawa, H., Souda, S., Aozasa, K., Monden, M., and Sugiyama, H. Overexpression of the Wilms' tumor gene WT1 in colorectal adenocarcinoma. Cancer Science, 94: 712-717, 2003.[Non-patent Document 13] Oji, Y., Miyoshi, S., Takahashi, E., Koga, S., Nakano, Y., Shintani, Y., Hirabayashi, H., Matsumura, A., Iuchi, K., Ito, K., Kishimoto, Y., Tsuboi, A., Ikegame, K., Hosen, N., Oka, Y., Ogawa, H., Maeda, H., Hayashi, S., Kawase, I., and Sugiyama, H. Absence of mutations in the Wilms' tumor gene WT1 in de novo non-small cell lung cancers. Neoplasma, 51:17-20, 2004.[Non-patent Document 14] Oji, Y., Miyoshi, Y., Kiyotoh, E., Koga, S., Nakano, Y., Ando, A., Hosen, N., Tsuboi, A., Kawakami, M., Ikegame, K., Oka, Y., Ogawa, H., Noguchi, S., and Sugiyama, H. Absence of mutations in the Wilms' tumor gene WT1 in primary breast cancer. Jpn Clin Oncol, 34:74-7, 2004.[Non-patent Document 15] Oji Y, Suzuki T, Nakano Y, Maruno M, Nakatsuka S, Jomgeow T, Abeno S, Tatsumi N, Yokota A, Aoyagi S, Nakazawa T, Ito K, Kanato K, Shirakata T, Nishida S, Hosen N, Kawakami M, Tsuboi A, Oka Y, Aozasa K, Yoshimine T, Sugiyama H, Overexpression of the Wilms' tumor gene WT1 in primary astrocytic tumors. Cancer Sci. 95:822-7, 2004.[Non-patent Document 16] Oji Y. Yano M, Nakano Y, Abeno S, Nakatsuka S, Ikeba A, Yasuda T, Fujiwara Y. Takiguchi S, Yamamoto H, Fujita S, Kanato K, Ito K, Jomgeow T, Kawakami M, Tsuboi A, Shirakata T, Nishida S, Hosen N, Oka Y, Aozasa K, Monden M, Sugiyama H., Overexpression of the Wilms' tumor gene WT1 in esophageal cancer. Anticancer Res. 24:3103-8, 2004.[Non-patent Document 17] Oji Y, Nakamori S, Fujikawa M, Nakatsuka S, Yokota A, Tatsumi N, Abeno S, Ikeba A, Takashima S, Tsujie M, Yamamoto H, Sakon M, Nezu R, Kawano K, Nishida S, Ikegame K, Kawakami M, Tsuboi A, Oka Y, Yoshikawa K, Aozasa K, Monden M, Sugiyama H. Overexpression of the Wilms' tumor gene WT1 in pancreatic ductal adenocarcinoma. Cancer Sci. 95:583-7, 2004.